Nivolumab + Trametinib (+/- Ipilimumab) for Colorectal Cancer

(CheckMate 9N9 Trial)

No longer recruiting at 106 trial locations

Overseen By Mohd Khushman, Site 0022

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Bristol-Myers Squibb

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: BRAF V600, Brain metastases, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of combining nivolumab (Opdivo) and trametinib (Mekinist), with or without ipilimumab (Yervoy), for individuals with previously treated metastatic colon or rectal cancer. Researchers aim to determine if this medication combination can more effectively target and treat metastatic colorectal cancer. Participants may qualify if they have stage IV colorectal cancer that has been previously treated and can be measured for changes. As a Phase 1, Phase 2 trial, this research seeks to understand how the treatment works in people and to measure its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on certain treatments like corticosteroids or other immunosuppressive drugs within 14 days before starting the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of nivolumab and trametinib is generally well-tolerated, with most people handling it without major issues. Long-term studies indicate it has a safe profile. For instance, in melanoma patients using similar treatments, only a small number (2.5%) experienced infusion-related reactions, suggesting that serious side effects are rare.

However, when ipilimumab is added to nivolumab and trametinib, studies have shown a higher rate of serious side effects, with 59% of patients experiencing significant reactions. Despite this, the FDA has approved the combination for other types of cancer, indicating a recognized level of safety.

These treatments are undergoing further testing in clinical trials to ensure safety and effectiveness for colorectal cancer. While some side effects may occur, the trials aim to weigh these against the potential benefits in fighting cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments involving nivolumab, trametinib, and ipilimumab for colorectal cancer because they offer a different approach from standard chemotherapy or targeted therapies like bevacizumab and cetuximab. Nivolumab and ipilimumab are immune checkpoint inhibitors that help the immune system recognize and attack cancer cells, while trametinib targets a specific pathway that cancer cells use to grow. This combination may enhance the body's ability to fight the cancer more effectively than current treatments. Additionally, the use of immune checkpoint inhibitors represents a novel mechanism of action that could lead to improved outcomes for patients who have not responded well to existing therapies.

What evidence suggests that this trial's treatments could be effective for colorectal cancer?

Research has shown that nivolumab, especially when combined with ipilimumab, effectively treats a type of colorectal cancer known as microsatellite instability-high (MSI-H). In this trial, some participants will receive nivolumab and trametinib. Studies have found that this combination allows patients to live without their cancer worsening for an average of 4.3 months and have an average overall survival of 13.6 months in certain cancers. Other participants will receive nivolumab, trametinib, and ipilimumab, a combination approved for treating advanced colorectal cancer, highlighting its potential benefits. These treatments enhance the immune system's ability to fight cancer cells, offering hope for those with advanced colorectal cancer. ^{2 6 7 8 9}

Who Is on the Research Team?

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Are You a Good Fit for This Trial?

This trial is for individuals with Stage IV colorectal cancer that has spread and was previously treated. They must have measurable disease, be in good physical condition (ECOG 0-1), and not have certain genetic mutations (BRAF V600). People can't join if they've had brain metastases, need systemic steroids or immunosuppressants, are allergic to the drugs being tested, or have used checkpoint inhibitors/MEK inhibitors before.

Inclusion Criteria

I am fully active or restricted in physically strenuous activity but can do light work.

My cancer's microsatellite status was checked using standard methods.

My colorectal cancer is confirmed to be in stage IV and has been previously treated.

Exclusion Criteria

I have had interstitial lung disease or pneumonitis.

I have an autoimmune disease.

History of allergy or hypersensitivity to study drug components

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nivolumab in combination with trametinib with or without ipilimumab

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab
• Trametinib

Trial Overview The study tests nivolumab combined with trametinib, with some participants also receiving ipilimumab. It aims to see how well these drugs work together in treating colorectal cancer that's spread after previous treatment. Participants will be randomly assigned to different drug combinations.

How Is the Trial Designed?

Group I: Part 2 Cohort 5 (3L): Regorafenib Experimental Treatment 1 Intervention

Group II: Part 2 Cohort 4 (3L): nivolumab + ipilimumab + trametinib Experimental Treatment 3 Interventions

Group III: Part 1B Cohort 6 (2L): nivolumab + ipilimumab + trametinib Experimental Treatment 3 Interventions

Group IV: Part 1A Cohort 3 (2L): nivolumab + ipilimumab + trametinib Experimental Treatment 3 Interventions

Group V: Part 1A Cohort 2 2nd Line (2L): nivolumab + ipilimumab + trametinib Experimental Treatment 3 Interventions

Group VI: Part 1 Cohort 1 3rd Line (3L): nivolumab + trametinib Experimental Treatment 2 Interventions

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

Bristol-Myers Squibb

Lead Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

Published Research Related to This Trial

Ipilimumab is an immunotherapy that works by inhibiting CTLA-4, leading to enhanced immune system activation, which can effectively treat advanced melanoma and other cancers.

Common side effects of ipilimumab are mostly mild to moderate (grade I or II) and include immune-mediated reactions like inflammatory diarrhea and pruritus, but serious side effects can be managed effectively with corticosteroids or other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab for advanced melanoma: a nursing perspective. Ledezma, B.[2017]

Immunotherapy using PD-1 inhibitors shows promising efficacy in treating high-level microsatellite instability (MSI-H) colorectal cancers (CRCs), with a 40% objective response rate in MSI-H patients compared to 0% in microsatellite stable (MSS) patients.

The studies indicate that while PD-1 inhibitors may benefit MSI-H mCRC patients, there is currently no evidence supporting their effectiveness in MSS CRCs, highlighting the need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Potential Value of Immunotherapy in Colorectal Cancers: Review of the Evidence for Programmed Death-1 Inhibitor Therapy. Toh, JWT., de Souza, P., Lim, SH., et al.[2022]

In a phase II study involving 45 patients with MSI-H/dMMR metastatic colorectal cancer, the combination of nivolumab and low-dose ipilimumab showed a high objective response rate of 69% and a disease control rate of 84%, indicating strong efficacy as a first-line treatment.

The treatment was well tolerated, with only 22% of patients experiencing grade 3-4 treatment-related adverse events, and 74% of responders maintained their response at the time of data cutoff, suggesting durability of the treatment effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase II CheckMate 142 Study. Lenz, HJ., Van Cutsem, E., Luisa Limon, M., et al.[2022]

Nivolumab and ipilimumab, two FDA-approved immunotherapeutic agents targeting PD-1 and CTLA-4, are effective in treating various cancers but can cause significant immune-related adverse effects (irAEs).

In a case study of a 66-year-old female patient, steroid-resistant colitis induced by these checkpoint inhibitors was successfully treated with infliximab, highlighting a potential management strategy for severe irAEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Immune Checkpoint Inhibitor Induced Colitis with Infliximab. Tidwell, C., Gutnik, S.[2020]

In a pooled analysis of 1332 patients with advanced non-small-cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab showed a median overall survival (OS) of 18.6 months and a 3-year OS rate of 35%, indicating significant long-term survival benefits compared to traditional chemotherapy.

The study found that patients who responded to treatment at 6 months had markedly better survival rates, with a 3-year OS of 66% for responders, highlighting the importance of early response in predicting long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. Borghaei, H., Ciuleanu, TE., Lee, JS., et al.[2023]

A systematic review of 14 randomized controlled trials found that combining nivolumab (NIVO) with ipilimumab (IPI) significantly increases the risk of treatment-related adverse events (TRAEs) compared to NIVO alone, with an overall risk ratio of 1.11 for any grade TRAEs and 1.95 for severe (grade 3 or 4) TRAEs.

Specific adverse events were notably higher with the combination therapy, including colitis (RR = 4.52), pneumonitis (RR = 3.06), and diarrhea (RR = 1.68), indicating that while the combination may be effective, it comes with increased safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events Induced by Nivolumab Plus Ipilimumab vs. Nivolumab Monotherapy among Cancer Patients: A Systematic Review and Meta-Analysis. Kamat, S., Patel, J., Brown, BR., et al.[2022]

Combining nivolumab and ipilimumab shows improved effectiveness in treating metastatic melanoma compared to using either drug alone, based on a retrospective analysis of approximately 7700 patients.

The combination therapy presents a safety profile that includes immune-related adverse events from both drugs, indicating that while the combination is effective, it also carries a heightened risk of toxicity that needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. Soldatos, TG., Dimitrakopoulou-Strauss, A., Larribere, L., et al.[2022]

Nivolumab, a PD-1 inhibitor, is approved for treating various cancers, including metastatic colorectal cancer with specific genetic markers (deficient mismatch repair or microsatellite-instability high).

The FDA granted accelerated approval for nivolumab in July 2017 for patients with this type of colorectal cancer who have not responded to standard chemotherapy, highlighting its potential efficacy in a challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab in the treatment of microsatellite instability high metastatic colorectal cancer. Mehrvarz Sarshekeh, A., Overman, MJ., Kopetz, S.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03377361

NCT03377361 | An Investigational Immuno-therapy Study ... The purpose of this study is to investigate treatment with nivolumab in combination with trametinib with or without ipilimumab in participants with previously ...

2. opdivohcp.com opdivohcp.com/efficacy/crc/opdivo-yervoy

Efficacy in Colorectal Cancer (CRC) - OPDIVO® (nivolumab) At the 47.0-month median follow-up, sustained separation of curves was observed for up to 3 years, but these data were not powered to detect differences in the ...

3. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-msi-h-or-dmmr-colorectal-cancer

FDA approves nivolumab with ipilimumab for unresectable ... The major efficacy outcome measure was progression-free survival (PFS) assessed by blinded independent central review (BICR) per RECIST v1.1 in ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9994043/

Is the combination of immunotherapy with conventional ... This review focused on the drugs that may modulate the immune response and show specific efficacy in the treatment of colorectal cancer.

5. withpower.com withpower.com/trial/phase-2-colorectal-neoplasms-1-2018-e6888

Nivolumab + Trametinib (+/- Ipilimumab) for Colorectal ... Research shows that Nivolumab, especially when combined with Ipilimumab, is effective for treating a specific type of colorectal cancer called microsatellite ...

6. opdivohcp.com opdivohcp.com/efficacy/crc

Efficacy Data for Colorectal Cancer (CRC) - Opdivo In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In HCC ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9941044/

Combined PD-1, BRAF and MEK inhibition in BRAFV600E ... Patients with BRAFV600E-mutated colorectal cancer have encouraging overall response rates to inhibition of PD-1, BRAF and MEK, with ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4811023/

Survival, Durable Tumor Remission, and Long-Term Safety in ... Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with ...

9. cell.com cell.com/cancer-cell/fulltext/S1535-6108(25)00340-X

Phase 1/2 trial of encorafenib, cetuximab, and nivolumab in ... Notably, overall disease control rate was 96%, indicating that the addition of immunotherapy nivolumab confers durable response as we ...